Lipid droplet dynamics control type I interferon responses and viperin expression to suppress viral replication.

Viral infection triggers innate immune responses that are essential for restricting early pathogen replication. Lipid droplets (LDs), traditionally recognized as neutral lipid storage organelles, have recently emerged as regulators of immune signaling. In this study, we investigated the modulatory role of LDs in antiviral immunity using porcine reproductive and respiratory syndrome virus (PRRSV) and pseudorabies virus (PRV) as models. We demonstrated that oleic acid (OA)-induced LD accumulation significantly enhanced type I interferon (IFN) responses and suppressed viral replication. Mechanistically, increased LD content potentiated the activation of both the RIG-I/MDA5 and cGAS-STING signaling pathways. Moreover, LD accumulation led to upregulation of viperin, a key interferon-inducible antiviral protein. Pharmacological inhibition of LD formation or DGAT2 activity reduced viperin expression and impaired antiviral efficacy, indicating that LD dynamics are functionally linked to the antiviral state. Collectively, our findings uncover an important role of LDs in coordinating innate immune signaling and viperin-mediated antiviral defense, positioning LDs as potential therapeutic targets for enhancing host immunity against viral infections.